The purpose of this proposal is to investigate the effects of exercise training in lean, non diabetic individuals who have insulin resistance, but normal glucose tolerance. Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). It is not appreciated, however, that insulin resistance of a similar nature and magnitude also occurs in up to 25% of lean, non-diabetic individuals with normal glucose tolerance. In this group, insulin resistance, in the absence of hyperglycemia, predisposes them to: 1) T2D; 2) the Metabolic Syndrome X (hypertension, dyslipidemia, and coronary artery disease); and 3) cancer. However, in these non diabetics, intervention strategies have not been developed, and the biochemical mechanisms of insulin resistance have not been extensively studied. For two major reasons therefore we propose to investigate this insulin resistant group. First, because they are at a higher risk for clinical disease than insulin sensitive subjects, it is important to clearly document that exercise is a beneficial intervention for them. Second, in this group, an analysis of their insulin resistance is not confounded (as in the usual T2D patient) by metabolic abnormalities resulting from obesity or hyperglycemia. Therefore, in these subjects, we plan to measure whole body insulin sensitivity by insulin clamp, and the major components of the insulin signaling system in muscle both before and after exercise training. The components to be studied are: the insulin receptor; IRS proteins; PI 3-kinase; PKB/AKT; and GLUT 4. In addition, we will study the major known regulators of the system: adiponectin; PTP 1B; PC-l; IKK; NF-KB; and PKC. Next these resistant individuals will undergo 14 weeks of exercise training to increase insulin sensitivity. After training they will be restudied and the results obtained compared to two control groups: non-exercised, insulin resistant subjects; and insulin sensitive subjects. We believe that these studies will: 1) document the beneficial improvements insulin sensitivity that occur with exercise training in insulin resistant, non diabetic subjects; 2) further our understanding of the biochemical defects that underlie insulin resistance; and 3) have the potential to reveal new cellular targets for therapeutic intervention.